The broad goal of this project is to continue to investigate the neuroendocrine and gonadal regulation of reproduction in women, focusing on the complex interrelationships between FSH, estradiol and the inhibins. There is now evidence that both estradiol and the inhibins contribute to the negative feedback control of FSH in women. However, their relative roles in the precise control of FSH during the follicular and luteal phases of the normal menstrual cycle have not been delineated. There are two unique circumstances in which we have shown that the coordinated secretion of estradiol and the inhibins is altered: in reproductive aging, estradiol levels are increased in the presence of low levels of inhibin while in African-American women, normal reproductive cycles are characterized by increased estradiol relative to Caucasian women in the face of identical levels of inhibin. Determining the mechanisms responsible for these changes will provide us with important insights into the interactions of inhibin, estradiol and gonadotropins in normal reproductive physiology. Aim 1 will determine the relative contributions of estradiol and the inhibins to the negative feedback regulation of FSH secretion during the follicular and luteal phases of the normal menstrual cycle using normal and GnRH-deficient women in whom estrogen secretion is altered by aromatase blockade. Aim 2 will seek to elucidate the mechanisms underlying the dichotomy between estradiol and inhibin secretion in reproductive aging by investigating inhibin and estradiol secretion in response to fixed FSH stimulation and by determining the number of granulosa cells and inhibin subunit expression and aromatase function and expression in antral and preovulatory follicles as a function of reproductive aging. Aim 3 will determine the feedback and feed-forward interactions between FSH, estradiol and the inhibins that result in an increase in estradiol levels across normal reproductive cycles in African- American women. Feedback will be examined using an estrogen infusion protocol while feed-forward will examine the control of estradiol and inhibin secretion in preovulatory follicles. Understanding the feedback and feed-forward dynamics of the hypothalamic-pituitary and ovarian components of the reproductive system is critical to an appreciation of the pathophysiology of reproductive disorders. This information is ultimately required for the design of therapeutic options for patients with reproductive disorders including infertility.